The specific aims of this competitive renewal proposal are to develop stimuli-responsive bioconjugates and complexes as molecular switches for controlling (a) biorecognition processes ("bioactivity switches") and (b) intracellular trafficking of biomolecules ("membrane switches"). Bioactivity switches are responsive polymer-engineered protein (RP-EP) conjugates that can be stimulated to turn protein activity on and off , or trigger release of bound ligand. Applications as on-off switches include affinity separations, diagnostics, drug targeting, and enzyme processes, such as PCR, industrial enzyme processes and detergent and fabric finishing processes. Actions of bioactivity switches as triggered release systems include the delivery of: biotinylated agents, affinity biomolecules, drugs, chemical agents, enzyme substrates, products or inhibitors, and signals. Such actions have many diverse uses in medicine, biotechnology and industry. Membrane switches are pH-responsive polymer bioconjugates or complexes with drug carriers that disrupt endosomal membranes to enhance intracellular delivery of DNA or protein drugs. This action should increase the efficacies of gene, antisense oligonucleotide, and cancer therapies.